Structure-guided redesign of an antischistosomal drug New drugs to treat schistosomiasis, a disease caused by the blood flukes Schistosoma mansoni (Sm), Schistosoma haemtobium (Sh) and Schistosoma japonicum (Sj), are urgently needed because only treatment with a monotherapy (Praziquantel - PZQ) is used and effective vaccines are not available. Oxamniquine (OXA) has an excellent safety record and it is extremely effective against Sm, but it is no longer used because unlike PZQ, OXA is ineffective against Sh and Sj. Hycanthone, a drug related to OXA, is active against Sm and Sh and inactive against Sj, but its unfavorable hepatotoxicity profile precludes use as a therapeutic agent. OXA and HC are pro-drugs that become activated by a schistosome enzyme. We recently identified the OXA-activating enzyme in Sm as a sulfotransferase (SmSULT) and we also identified its homologs in Sh (ShSULT) and Sj (SjSULT). Our 1.75 crystal structure of the SmSULT*cofactor*OXA complex reveals the molecular basis for OXA activation and drug action in Sm. ShSULT and SjSULT enzymes share 71% and 58% sequence identity with SmSULT, respectively. The high degree of sequence and structural similarity observed between Sm-, Sh- and SjSULT suggests these structures can be used as templates in the design of modified OXA-derivatives that will kill Sm, Sh, and Sj. The methods used to achieve this goal include (i) comparative structural and biochemical analyses of enzyme*cofactor*OXA complexes, (ii) experimental determination of the critical amino acids responsible for species-specific drug action, and (iii) iterative cycles of structure-guided design paired with in vitro studies of drug activation and parasite killing, followed by syntheses of novel OXA derivatives/analogs with final testing in infected rodents. A pan-specific OXA derivative would provide an alternative to PZQ for schistosome treatment, or a partner for PZQ to retard the evolution of resistance and make chemotherapy more effective.